The helical nature of DNA causes a topological problem for its replication. Watson and Crick were well aware of this potential problem, and in 1953 they stated: Since the two chains in our model are intertwined, it is essential for them to untwist if they are to separate... Although it is difficult at the moment to see how these processes occur without everything getting tangled, we do not feel that this objection will be insuperable. We now know that this problem is solved by the DNA topoisomerases, first reported in 1971 by James Wang with the discovery of bacterial topoisomerase I. Over the past ~40 years these enzymes have been found in all organisms (prokaryotes, eukaryotes, viruses and archaea) and to perform roles that are vital for survival, supporting replication, transcriptio and other processes where DNA topological problems need to be resolved. The enzymes are 'marvelous molecular machines' catalyzing the seemingly magical task of passing one piece of DNA through another to catalyze changes in DNA topology. Some of the enzymes are molecular motors, transducing the free energy of ATP hydrolysis into torsional stress in DNA (supercoiling). Although the outline of their mechanisms has been established, a great deal is unknown and emerging technologies, such as single-molecule methods, need to be applied to gain a deeper understanding of these enzymes and their roles in cellular processes. Topoisomerases have become key drug targets both for anti-bacterial and anti-cancer chemotherapy. This is due to their essential nature and their mechanism of action, which involves transient DNA cleavage that, if disrupted, can lead to highly cytotoxic events. Study of these enzymes in the context of myriad cellular processes is critical in research leading to the development of new chemotherapeutic agents. The inaugural 2014 DNA Topoisomerases in Biology and Medicine of Cancer Gordon Research Conference strives to attract scientists from a broad range of disciplines, highlighting recent advances in structural biology of topoisomerases and the application of single-molecule technologies to promote exciting new research on understanding topoisomerases at the detailed molecular level. At other end of the scale, advances in imaging technologies and proteomics/genomics enable new insights into the cellular roles of topoisomerases and their significance in human cancers. The meeting will be chaired by Prof. Tony Maxwell (John Innes Centre), with Dr. Mary-Ann Bjornsti (University of Alabama at Birmingham) as Vice Chair, both leaders in the topoisomerase field, representing bacterial enzymes and antibiotics, and eukaryotic enzymes and anti-tumor agents, respectively. This application seeks funds to support the participation of exceptionally talented young investigators (students, post-docs and fellows) from diverse backgrounds, to engage their imagination and interactions with leaders in the field. The informal nature of Gordon Research Conferences and the strong emphasis placed on high-caliber science presented with thought-provoking commentary ensures a highly interactive meeting to stimulate new perspectives on topoisomerases in biology and medicine.